Inhibition of mTORC2 component RICTOR impairs tumor growth in pancreatic cancer models
Schmidt KM, Hellerbrand C, Ruemmele P, Michalski CW, Kong B, Kroemer A, Hackl C, Schlitt HJ, Geissler EK, Lang SA (2017)
Publication Type: Journal article
Publication year: 2017
Journal
Book Volume: 8
Pages Range: 24491-24505
Journal Issue: 15
DOI: 10.18632/oncotarget.15524
Abstract
Mammalian Target of Rapamycin complex 2 (mTORC2) and its regulatory component Rapamycin-insensitive companion of mTOR (RICTOR) are increasingly recognized as important players in human cancer development and progression. However, the role of RICTOR in human pancreatic ductal adenocarcinoma (PDAC) is unclear so far. Here, we sought to analyze the effects of RICTOR inhibition in human pancreatic cancer cell lines in vitro and in vivo. Furthermore, RICTOR expression was determined in human PDAC samples. Results demonstrate that depletion of RICTOR with siRNA (transient knock-down) or shRNA (stable knock-down) has an inhibitory effect on tumor growth in vitro. Moreover, RICTOR inhibition led to impaired phosphorylation/activity of AGC kinases (AKT, SGK1). Interestingly, hypoxia-induced expression of hypoxia-induced factor-1? (HIF-1?) was diminished and secretion of vascular-endothelial growth factor-A (VEGF-A) was impaired upon targeting RICTOR. Stable RICTOR knock-down led to significant inhibition of tumor growth in subcutaneous and orthotopic tumor models which was accompanied by significant reduction of tumor cell proliferation. Finally, immunohistochemical analyses of 85 human PDAC samples revealed significantly poorer survival in patients with higher RICTOR expression. In conclusion, these findings provide first evidence for mTORC2/RICTOR as an attractive novel target for treatment of human PDAC.
Involved external institutions
Universitätsklinikum Regensburg
Germany (DE)
Technische Universität München (TUM)
Germany (DE)
Ruprecht-Karls-Universität Heidelberg
Germany (DE)
Germany (DE)
Technische Universität München (TUM)
Germany (DE)
Ruprecht-Karls-Universität Heidelberg
Germany (DE)
How to cite
APA:
Schmidt, K.M., Hellerbrand, C., Ruemmele, P., Michalski, C.W., Kong, B., Kroemer, A.,... Lang, S.A. (2017). Inhibition of mTORC2 component RICTOR impairs tumor growth in pancreatic cancer models. Oncotarget, 8(15), 24491-24505. https://doi.org/10.18632/oncotarget.15524
MLA:
Schmidt, Katharina M., et al. "Inhibition of mTORC2 component RICTOR impairs tumor growth in pancreatic cancer models." Oncotarget 8.15 (2017): 24491-24505.
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